Evolution of flash visual evoked potentials to monitor visual pathway integrity during tumor resection: illustrative cases and literature review.

Flash visual evoked potentials (fVEPs) provide a means to interrogate visual system functioning intraoperatively during tumor resection in which the optic pathway is at risk for injury. Due to technical limitations, fVEPs have remained underutilized in the armamentarium of intraoperative neurophysiological monitoring (IONM) techniques. Here we review the evolution of fVEPs as an IONM technique with emphasis on the enabling technological and intraoperative improvements. A combined approach with electroretinography (ERG) has enhanced feasibility of fVEP neuromonitoring as a practical application to increase safety and reduce error during tumor resection near the prechiasmal optic pathway. The major advance has been towards differentiating true cases of damage from false findings. We use two illustrative neurosurgical cases in which fVEPs were monitored with and without ERG to discuss limitations and demonstrate how ERG data can clarify false-positive findings in the operating room. Standardization measures have focused on uniformity of photostimulation parameters for fVEP recordings between neurosurgical groups.

Toward Generalizable Trajectory Planning for Human Intracerebral Trials and Therapy.

INTRODUCTION: Stereotactic neurosurgical techniques are increasingly used to deliver biologics, such as cells and viruses, although standardized procedures are necessary to ensure consistency and reproducibility. OBJECTIVE: We provide an instructional guide to help plan for complex image-guided trajectories; this may be of particular benefit to surgeons new to biologic trials and companies planning such trials. METHODS: We show how nuclei can be segmented and multiple trajectories with multiple injection points can be created through a single or multiple burr hole(s) based on preoperative images. Screenshots similar to those shown in this article can be used for planning purposes and for quality control in clinical trials. RESULTS: This method enables the precise definition of 3-D target structures, such as the putamen, and efficient planning trajectories for biologic injections. The technique is generalizable and largely independent of procedural format, and thus can be integrated with frame-based or frameless platforms to streamline reproducible therapeutic delivery. CONCLUSIONS: We describe an easy-to-use and generalizable protocol for intracerebral trajectory planning for stereotactic delivery of biologics. Although we highlight intracerebral stem cell delivery to the putamen using a frame-based stereotactic delivery system, similar strategies may be employed for different brain nuclei using different platforms. We anticipate this will inform future advanced and fully automated neurosurgical procedures to help unify the field and decrease inherent variability seen with manual trajectory planning.

Treatment Strategies for Generator Pocket Pain.

OBJECTIVE: Generator site pain is a relatively common phenomenon in patients undergoing spinal cord stimulation (SCS) that complicates management and effective pain relief. This pain may be managed conservatively, with repositioning of the battery and, in some cases, with explant. Here we explore our experience with management of generator site pain ("pocket pain") in a large single-center study. METHODS: All SCS permanent implants and implantable pulse generator (IPG) placements over 9 years were reviewed. Of 785 cases, we identified 43 patients with pocket pain (5.5%). Demographics and treatments of the pocket pain cohort were analyzed. RESULTS: The mean age (± SEM) of the pocket pain cohort was 46.86 ± 1.06, and there were 10/33 males/females. Females were overrepresented in pocket pain cohort (76.7%) when compared with the total SCS cohort (59.0%) (X2 = 5.93, P = 0.015). Diagnosis included failed back surgery syndrome (51.2%), complex regional pain syndrome (23.3%), and chronic neuropathic pain (25.5%). No patients improved with conservative therapy. All patients either went on to revision (n = 23) or explant (n = 20). Time from initial surgery to development of pocket pain was 7.5 months (range: 0.3-88) and from pocket pain to revision surgery was 4.5 months (range: 0.4-26). In addition, significantly more pocket pain patients (65.1%) had workers' compensation (WC) insurance compared with patients without pocket pain (24.9%) (X2 = 33.3, P < 0.001). CONCLUSION: In our institutional experience, pocket pain was inadequately managed with conservative treatments. Being female and having SCS filed under WC increased risk of pocket pain. Future work will explore the nuances in device placement based on body shape and manual activity responsibilities.

Functional replacement of fission yeast γ-tubulin small complex proteins Alp4 and Alp6 by human GCP2 and GCP3.

Microtubule-organizing centers such as the γ-tubulin ring complex (γ-TuRC) act as a template for polarized growth and regulation of microtubules that are essential for diverse cellular structures and processes in eukaryotes. New structural models of the budding yeast γ-tubulin small complex (γ-TuSC) of the γ-TuRC combined with functional studies done in multiple eukaryotes are revealing the first mechanistic clues into control of microtubule nucleation and organization. Cross-species studies of human and budding yeast γ-TuSC proteins in fission yeast revealed conserved and divergent structural and functional features of the γ-TuSC. We show genetically that GCP3/Spc98 function is fully conserved with Alp6 across species but that functional differences exist between GCP2/Spc97 and Alp4. By further analysis of human γ-TuSC proteins, we found that GCP3 assembles normally into the >2000 kDa fission yeast γ-TuRC and that the GCP3 gene replaces fission yeast alp6. Interestingly, human GCP2 replaces the essential alp4 gene but is unable to rescue a normally recessive G1 defect of the alp4-1891 allele that results in loss of γ-TuRC from poles in subsequent cell cycles. Biochemically, GCP2 incorporation into fission yeast γ-TuRC is limited in the presence of Alp4; instead, the bulk of GCP2 fractionates as smaller complexes. By generating a functional Alp4-GCP2 chimeric protein we determined that the GCP2 N-terminal domain limits its ability to fully displace or compete with Alp4 during γ-TuRC assembly. Our findings have broad importance for understanding the essential domains of γ-TuSC proteins in the γ-TuRC mechanism.

Embryonic Spinal Cord Innervation in Human Trunk Organogenesis Gastruloids: Cardiac Versus Enteric Customization and Beyond.

Trunk-biased human gastruloids provide the ability to couple developmentally relevant spinal neurogenesis and organ morphogenesis via spatiotemporal self-organization events from derivatives of the three germ layers. The multi-lineage nature of gastruloids provides the full complexity of regulatory signaling cues that surpasses directed organoids and lays the foundation for an ex vivo self-evolving system. Here we detail two distinct protocols for trunk-biased gastruloids from an elongated, polarized structure with coordinated organ-specific neural patterning. Following an induction phase to caudalize iPSCs to trunk phenotype, divergent features of organogenesis and end-organ innervation yield separate models of enteric and cardiac nervous system formation. Both protocols are permissive to multi-lineage development and allow the study of neural integration events within a native, embryo-like context. We discuss the customizability of human gastruloids and the optimization of initial and extended conditions that maintain a permissive environment for multi-lineage differentiation and integration.

Intrathecal placement of percutaneous spinal cord stimulation leads: illustrative cases.

BACKGROUND: Spinal cord stimulation (SCS), including the percutaneous placement of epidural stimulation leads, has been increasingly utilized to treat chronic pain. Although lead migration is a well-characterized complication, few studies have reported on malpositioned leads in the intrathecal space. Here, the authors discuss two cases of intrathecal lead placement necessitating surgical revision. OBSERVATIONS: This report is a two-case series on the inadvertent placement of percutaneous SCS leads in the intrathecal space. The authors describe the identification of malpositioned leads, describe the clinical presentation, characterize stimulation parameters, and report improvement following neurosurgical revision for each case. Two patients originally presenting with chronic low-back pain underwent percutaneous SCS lead implantation. Both patients presented with atypical pain symptoms in the acute to subacute postprocedural period, raising suspicion for malpositioned leads. Imaging was consistent with intrathecal malpositioning. Both patients underwent revision surgery resulting in symptomatic improvement. LESSONS: Indicators of malpositioned thoracic SCS leads in the intrathecal space include thoracoabdominal or flank pain exacerbated by movement, insufficient pain relief versus that in the SCS trial, very low electrode impedances, direct visualization on imaging, and lack of epidural lead visualization following laminectomy. Revision options include removal of the intrathecal leads and the surgical placement of a paddle electrode in the epidural space. https://thejns.org/doi/10.3171/CASE24275.

Axonal transport during injury on a theoretical axon.

Neurodevelopment, plasticity, and cognition are integral with functional directional transport in neuronal axons that occurs along a unique network of discontinuous polar microtubule (MT) bundles. Axonopathies are caused by brain trauma and genetic diseases that perturb or disrupt the axon MT infrastructure and, with it, the dynamic interplay of motor proteins and cargo essential for axonal maintenance and neuronal signaling. The inability to visualize and quantify normal and altered nanoscale spatio-temporal dynamic transport events prevents a full mechanistic understanding of injury, disease progression, and recovery. To address this gap, we generated DyNAMO, a Dynamic Nanoscale Axonal MT Organization model, which is a biologically realistic theoretical axon framework. We use DyNAMO to experimentally simulate multi-kinesin traffic response to focused or distributed tractable injury parameters, which are MT network perturbations affecting MT lengths and multi-MT staggering. We track kinesins with different motility and processivity, as well as their influx rates, in-transit dissociation and reassociation from inter-MT reservoirs, progression, and quantify and spatially represent motor output ratios. DyNAMO demonstrates, in detail, the complex interplay of mixed motor types, crowding, kinesin off/on dissociation and reassociation, and injury consequences of forced intermingling. Stalled forward progression with different injury states is seen as persistent dynamicity of kinesins transiting between MTs and inter-MT reservoirs. DyNAMO analysis provides novel insights and quantification of axonal injury scenarios, including local injury-affected ATP levels, as well as relates these to influences on signaling outputs, including patterns of gating, waves, and pattern switching. The DyNAMO model significantly expands the network of heuristic and mathematical analysis of neuronal functions relevant to axonopathies, diagnostics, and treatment strategies.

Corrigendum: Axonal transport during injury on a theoretical axon.

[This corrects the article DOI: 10.3389/fncel.2023.1215945.].

Direct Wave Intraoperative Neuromonitoring for Spinal Tumor Resection: A Focused Review.

At present, surgical resection of primary intramedullary spinal cord tumors is the mainstay of treatment. However, given the dimensional constraints of the narrow spinal canal and dense organization of the ascending and descending tracts, intramedullary spinal cord tumor resection carries a significant risk of iatrogenic neurological injury. Intraoperative neurophysiological monitoring (IONM) and mapping techniques have been developed to evaluate the functional integrity of the essential neural pathways and optimize the surgical strategies. IONM can also inform on impending harm to at-risk structures and can correlate with postoperative functional recovery if damage has occurred. Direct waves (D-waves) will provide immediate feedback on the integrity of the lateral corticospinal tract. In the present review, we have provided an update on the utility of D-waves for spinal cord tumor resection. We have highlighted the neuroanatomical and neurophysiological insights from the use of D-wave monitoring, the technical considerations and limitations of the D-wave technique, and multimodal co-monitoring with motor-evoked potentials and somatosensory-evoked potentials. Together with motor-evoked potentials, D-waves can help to guide the extent of tumor resection and provide intraoperative warning signs and alarm criteria to direct the surgical strategy. D-waves can also serve as prognostic biomarkers for long-term recovery of postoperative motor function. We propose that the use of D-wave IONM can contribute key findings for clinical decision-making during spinal cord tumor resection.

Intraoperative Monitoring of the External Urethral Sphincter Reflex: A Novel Adjunct to Bulbocavernosus Reflex Neuromonitoring for Protecting the Sacral Neural Pathways Responsible for Urination, Defecation and Sexual Function.

PURPOSE: Intraoperative bulbocavernosus reflex neuromonitoring has been utilized to protect bowel, bladder, and sexual function, providing a continuous functional assessment of the somatic sacral nervous system during surgeries where it is at risk. Bulbocavernosus reflex data may also provide additional functional insight, including an evaluation for spinal shock, distinguishing upper versus lower motor neuron injury (conus vs. cauda syndromes) and prognosis for postoperative bowel and bladder function. Continuous intraoperative bulbocavernosus reflex monitoring has been utilized to provide the surgeon with an ongoing functional assessment of the anatomical elements involved in the S2-S4 mediated reflex arc including the conus, cauda equina and pudendal nerves. Intraoperative bulbocavernosus reflex monitoring typically includes the electrical activation of the dorsal nerves of the genitals to initiate the afferent component of the reflex, followed by recording the resulting muscle response using needle electromyography recordings from the external anal sphincter. METHODS: Herein we describe a complementary and novel technique that includes recording electromyography responses from the external urethral sphincter to monitor the external urethral sphincter reflex. Specialized foley catheters embedded with recording electrodes have recently become commercially available that provide the ability to perform intraoperative external urethral sphincter muscle recordings. RESULTS: We describe technical details and the potential utility of incorporating external urethral sphincter reflex recordings into existing sacral neuromonitoring paradigms to provide redundant yet complementary data streams. CONCLUSIONS: We present two illustrative neurosurgical oncology cases to demonstrate the utility of the external urethral sphincter reflex technique in the setting of the necessary surgical sacrifice of sacral nerve roots.

A combined human gastruloid model of cardiogenesis and neurogenesis.

Multi-lineage development from gastruloids is enabling unprecedented opportunities to model and study human embryonic processes and is expected to accelerate ex vivo strategies in organ development. Reproducing human cardiogenesis with neurogenesis in a multi-lineage context remains challenging, requiring spatiotemporal input of paracrine and mechanical cues. Here we extend elongating multi-lineage organized (EMLO) gastruloids to include cardiogenesis (EMLOC) and describe interconnected neuro-cardiac lineages in a single gastruloid model. Contractile EMLOCs recapitulate numerous interlinked developmental features including heart tube formation and specialization, cardiomyocyte differentiation and remodeling phases, epicardium, ventricular wall morphogenesis, chamber-like structures and formation of a putative outflow tract. The EMLOC cardiac region, which originates anterior to gut tube primordium, is progressively populated by neurons in a spatial pattern mirroring the known distribution of neurons in the innervated human heart. This human EMLOC model represents a multi-lineage advancement for the study of coincident neurogenesis and cardiogenesis.

Generation of human elongating multi-lineage organized cardiac gastruloids.

Human elongating multi-lineage organized (EMLOC) gastruloid technology captures key aspects of trunk neurodevelopment including neural integration with cardiogenesis. We generate multi-chambered, contractile EMLOC gastruloids with integrated central and peripheral neurons using defined culture conditions and signaling factors. hiPSC colonies are primed by activating FGF and Wnt signaling pathways for co-induced lineages. EMLOC gastruloids are then initialized with primed cells in suspension culture using timed exposure to FGF2, HGF, IGF1, and Y-27632. Cardiogenesis is stimulated by FGF2, VEGF, and ascorbic acid. For complete details on the use and execution of this protocol, please refer to Olmsted and Paluh (2022).1.

Review of the Treatments for Central Neuropathic Pain.

Central neuropathic pain (CNP) affects millions worldwide, with an estimated prevalence of around 10% globally. Although there are a wide variety of treatment options available, due to the complex and multidimensional nature in which CNP arises and presents symptomatically, many patients still experience painful symptoms. Pharmaceutical, surgical, non-invasive, cognitive and combination treatment options offer a generalized starting point for alleviating symptoms; however, a more customized approach may provide greater benefit. Here, we comment on the current treatment options that exist for CNP and further suggest the need for additional research regarding the use of biomarkers to help individualize treatment options for patients.

Enhanced Recovery After Surgery (ERAS) for Cranial Tumor Resection: A Review.

Enhanced Recovery After Surgery (ERAS) protocols describe a standardized method of preoperative, perioperative, and postoperative care to enhance outcomes and minimize complication risks surrounding elective surgical intervention. A growing body of evidence is being generated as we learn to apply principles of ERAS standardization to neurosurgical patients. First applied in spinal surgery, ERAS protocols have been extended to cranial neuro-oncologic procedures. This review synthesizes recent findings to generate evidence-based guidelines to manage neurosurgical oncology patients with standardized systems and assess ability of these systems to coordinate multidisciplinary, patient-centric care efforts. Furthermore, we highlight the potential usefulness of multimedia, app-based communication platforms to facilitate patient education, autonomy, and team communication within each of the 3 settings.

Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine.

The ability to reliably repair spinal cord injuries (SCI) will be one of the greatest human achievements realized in regenerative medicine. Until recently, the cellular path to this goal has been challenging. However, as detailed developmental principles are revealed in mouse and human models, their application in the stem cell community brings trunk and spine embryology into efforts to advance human regenerative medicine. New models of posterior embryo development identify neuromesodermal progenitors (NMPs) as a major bifurcation point in generating the spinal cord and somites and is leading to production of cell types with the full range of axial identities critical for repair of trunk and spine disorders. This is coupled with organoid technologies including assembloids, circuitoids, and gastruloids. We describe a paradigm for applying developmental principles towards the goal of cell-based restorative therapies to enable reproducible and effective near-term clinical interventions.

Co-development of central and peripheral neurons with trunk mesendoderm in human elongating multi-lineage organized gastruloids.

Stem cell technologies including self-assembling 3D tissue models provide access to early human neurodevelopment and fundamental insights into neuropathologies. Gastruloid models have not been used to investigate co-developing central and peripheral neuronal systems with trunk mesendoderm which we achieve here in elongating multi-lineage organized (EMLO) gastruloids. We evaluate EMLOs over a forty-day period, applying immunofluorescence of multi-lineage and functional biomarkers, including day 16 single-cell RNA-Seq, and evaluation of ectodermal and non-ectodermal neural crest cells (NCCs). We identify NCCs that differentiate to form peripheral neurons integrated with an upstream spinal cord region after day 8. This follows initial EMLO polarization events that coordinate with endoderm differentiation and primitive gut tube formation during multicellular spatial reorganization. This combined human central-peripheral nervous system model of early organogenesis highlights developmental events of mesendoderm and neuromuscular trunk regions and enables systemic studies of tissue interactions and innervation of neuromuscular, enteric and cardiac relevance.

Fully Characterized Mature Human iPS- and NMP-Derived Motor Neurons Thrive Without Neuroprotection in the Spinal Contusion Cavity.

Neural cell interventions in spinal cord injury (SCI) have focused predominantly on transplanted multipotent neural stem/progenitor cells (NSPCs) for animal research and clinical use due to limited information on survival of spinal neurons. However, transplanted NSPC fate is unpredictable and largely governed by injury-derived matrix and cytokine factors that are often gliogenic and inflammatory. Here, using a rat cervical hemicontusion model, we evaluate the survival and integration of hiPSC-derived spinal motor neurons (SMNs) and oligodendrocyte progenitor cells (OPCs). SMNs and OPCs were differentiated in vitro through a neuromesodermal progenitor stage to mimic the natural origin of the spinal cord. We demonstrate robust survival and engraftment without additional injury site modifiers or neuroprotective biomaterials. Ex vivo differentiated neurons achieve cervical spinal cord matched transcriptomic and proteomic profiles, meeting functional electrophysiology parameters prior to transplantation. These data establish an approach for ex vivo developmentally accurate neuronal fate specification and subsequent transplantation for a more streamlined and predictable outcome in neural cell-based therapies of SCI.

Transplantable human motor networks as a neuron-directed strategy for spinal cord injury.

To repair neural circuitry following spinal cord injury (SCI), neural stem cell (NSC) transplantation has held a primary focus; however, stochastic outcomes generate challenges driven in part by NSC differentiation and tumor formation. The recent ability to generate regionally specific neurons and their support cells now allows consideration of directed therapeutic approaches with pre-differentiated and networked spinal neural cells. Here, we form encapsulated, transplantable neuronal networks of regionally matched cervical spinal motor neurons, interneurons, and oligodendrocyte progenitor cells derived through trunk-biased neuromesodermal progenitors. We direct neurite formation in alginate-based neural ribbons to generate electrically active, synaptically connected networks, characterized by electrophysiology and calcium imaging before transplantation into rodent models of contused SCI for evaluation at 10-day and 6-week timepoints. The in vivo analyses demonstrate viability and retention of interconnected synaptic networks that readily integrate with the host parenchyma to advance goals of transplantable neural circuitry for SCI treatment.

Can dogs and cats really help our spinal cord stimulation patients?

OBJECTIVES: Pet ownership has been shown to decrease morbidity and mortality in several aspects of health but has not been studied in chronic pain patients. We evaluate whether subjects who underwent spinal cord stimulation (SCS) and own a pet have improved outcomes compared to non-pet owners. METHODS: After obtaining IRB approval, we re-contacted 38 subjects who underwent SCS surgery with preoperative and 1-year postoperative data on Numerical Rating Scale (NRS), McGill Pain Questionnaire (MPQ), Oswestry Disability Index (ODI), Beck Depression Inventory (BDI), and Pain Catastrophizing scale (PCS). We examined influence of pets and pet ownership-specific behaviors on improvement in SCS outcomes. RESULTS: Patients included 24 males/14 females with a mean age of 59.9 ± 11.5 years. At mean follow-up of 12.2 months (range 10-14), there were improvements in NRS, ODI, BDI, PCS and MPQ. Twenty subjects owned pets and 18 did not; all believed pet ownership could improve health. Pet owners improved more on NRS-right now (p = 0.05) and BDI (p = 0.05), and were more satisfied with SCS (p = 0.04). No significant improvement was seen in ODI, MPQ, or PCS. However, PCS did improve in pet owners who exercised their pet (PCS-total, p < 0.01; PCS-helplessness, p < 0.01; PCS-rumination, p = 0.05; PCS-magnification, p = 0.02). CONCLUSIONS: We provide preliminary evidence that pet ownership is associated with improved pain, depression and SCS satisfaction. Exercising with a pet also appears to be beneficial in limiting pain catastrophizing. Pets show promise as a novel means to improve patient SCS outcomes.

Recommendations for Neuromodulation in Diabetic Neuropathic Pain.

Over 50% of the 34 million people who suffer from diabetes mellitus (DM) are affected by diabetic neuropathy. Painful diabetic neuropathy (PDN) impacts 40-50% of that group (8.5 million patients) and is associated with a significant source of disability and economic burden. Though new neuromodulation options have been successful in recent clinical trials (NCT03228420), still there are many barriers that restrict patients from access to these therapies. We seek to examine our tertiary care center (Albany Medical Center, NY, USA) experience with PDN management by leveraging our clinical database to assess patient referral patterns and utilization of neuromodulation. We identified all patients with a diagnosis of diabetes type 1 (CODE: E10.xx) or diabetes type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE: G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4) who saw endocrinology, neurology, and/or neurosurgery from January 1, 2019, to December 31, 2019. We then determined which patients had received pain medications and/or neuromodulation to divide the cohort into three groups: no treatment, conservative treatment, and neuromodulation treatment. The cohorts were compared with chi-square or one-way ANOVA with multiple comparisons to analyze the differences. A total of 2,635 PDN patients were identified, of which 700 received no treatment for PDN, 1,906 received medication(s), and 29 received neuromodulation (intrathecal therapy, spinal cord stimulation, or dorsal root ganglion stimulation). The patients who received pain medications for PDN visited neurology more often than the pain specialists. Of the patients that received neuromodulation, 24 had seen neurology, 6 neurology pain, and 3 anesthesia pain. They averaged 2.78 pain medications prior to implant. Approximately 41% of the patients in the conservative management group were prescribed three or more medications. Of the 1,935 treated patients, only 1.5% of the patients received neuromodulation. The patients on three or more pain medications without symptomatic relief may be potential candidates for neuromodulation. An opportunity, therefore, exists to educate providers on the benefits of neuromodulation procedures.